Anti-epileptic tertiary alicyclic urea derivative



Unite States Patent 3,098,791 Patented July 23, 1963 This invention relates to the use of certain cycloalkyl urea compounds for the treatment of epilepsy and to compositions including such compounds which are useful for this purpose. More particularly, this invention relates to methods for preventing disabling reactions such as epileptic seizures in patients afiiicted with epilepsy.

A number of drugs have been used more or less satisfactorily in the treatment and control of various types epilepsy. Many of the pharmaceutical compositions heretofore utilized in epilepsy therapy have proved to be effective therapeutic agents in one or more of the common forms of epilepsy. Even with the most satisfactory of these compositions, however, the use has been effective only in the prevention of epileptic seizures in certain for-ms of epilepsy. Thus, no known drug has been effective in the treatment of all forms of epilepsy. In the case of certain patients, in fact, it has been found that these patients are non-responsive or refractory to all known drugs for the treatment of epilepsy. Even where a drug has been found effective for treatment of the condition, in many instances the benefit to the patient has been found to be overshadowed by a high incidence of side efiects. Drowsiness, in particular, is a side effect which is frequently encountered by patients undergoing various types of anti-epileptic therapy. Other side effects encountered moreor less frequently include anorexia, nausea, vomiting, diarrhea, ataxia and various kinds of rashes. Then, to,'various withdrawal symptoms.

have been evidenced in cases where the drug being used in anti-epileptic therapy has been. changed and another drug substituted therefor. In many instances it has been necessary to utilize relatively high dosages of. the drugs used, which is undesirable from the standpoint of con venience of treatment. In some cases, drug metabolism has raised serious problems.

It is accordingly an objective of the instant invention to provide a means of prevention of epileptic seizures which has few of the disadvantages inherent in previous methods of therapy.

Another object of this invention is to provide formulations of chemo-therapeutic agents which are effective in the prevention or control of various forms of epileptic seizures.

Another object of this invention is to provide pharmaceutical compositions useful in the treatment of epileptic patients, particularly epileptic patients who have proved refractory to other drugs.

Yet, another object of this invention is to provide such pharmaceutical compositions in convenient dosage forms.

Other objects and advantages of this invention will become apparent in the course of the following disclosure and description.

It has now been tound that a series of tertiary alicyclic urea derivatives having the formula- CH2 R where n is 2 or 3 and R is lower alkyl, particularly methyl.

and ethyl, have outstanding anti-epileptic activity.

The compounds in question may be prepared. by various synthetic procedures exemplified by one or more of the reactions shown in the following equations:

(1) CH2 R Thus, it may 'beseenthat compounds of the class depicted above may be readily prepared using either the amine or the alkanol corresponding to the desired urea derivative. The reaction conditions used in conducting the various reactions, which may be used for the preparation of these compounds, are not in any way critical.

The preparative methods as well as the intended methods for use of these compounds will be exemplified in the following examples which, however, are intended merely for purposes of illustration and are not to be construed as in any way limiting the scope of this in- Mention. i

EXAMPLE 1 Preparation of ]-(1 -Methylcycl0 hexyl) Urea To 28.3 grams (0.25 mole) of 1-Inethylcyclohexyl amine in 200 ml. of ethyl alcohol was added 28.9 grams (0.275 mole) of nitrourea over a period of 30 minutes. The temperature was maintained at 4050 C. during the addition. The reaction mixture was gradually heated to reflux and approximately m1. of alcohol removed by distillation. Dilution of the residue with water precipitated a semi-solid mass which was filtered and dried under vacuum over calcium chloride. Crystallization from water gave 13 grams of crystalline product which melted at 99-l01 C.

Analysis.-Calcd. for C H N O: N, 17.92%. Found: N, 17.50%.

EXAMPLE 2 Preparation of 1-(1'-Methylcyclopentyl) Urea A quantity of 28.6 grams (10% excess) of nitrourea was added in portions to a solution of 24.5 grams of l-methylcyclopentylamine in 200 ml. of 95% ethyl alcohol initially heated to 45 C. As no detectable reaction occurred, the temperature was raised to' 55 C. 10 whereupon gas evolution indicated that the reaction was proceeding. The temperature was maintained at 55 C. during the remainder of the addition and was then gradually raised and the alcohol removed by distillation at reduced pressure. Benzene was then added and distillation continued until traces of water were removed. Filtration gave 29 grams of crystalline product and cooling of the benzene solution gave an additional 2.5 grams of crystalline material. The two crystalline fractions were combined, recrystallized from aqueous ethyl alcohol and gave 23.6 grams of product which melted at 175.5- 177.5 C.

Analysis.-Calcd. for C H N O: N, 19.70%. Found:

EXAMPLE 3 Preparation of 1-(1'-Ethylcyclopentyl) Urea A quantity of 46 grams of l-ethylcyclopentylamine was dissolved in 300 m1. of 95% ethyl alcohol and 48 grams of nitrourea was added in one portion. The reaction mixture was heated rapidly until there was vigorous gas evolution. When the vigorous reaction was completed, the solution was refluxed for minutes. The

mal seizures a day and only a grand mal seizure once in three to six months, the response of the petit mal seizures was evaluated. However, if the grand mal seizures were the more incapacitating, the response of the grand mal was evaluated. Each patient received -a CBC (complete blood count), urinalysis and urinary ur-obilinogen determination before the drug was started and at monthly intervlals. The drug was added to whatever anti-convulsant the patient had been taking. No patient reported any abnormality indicating a blood dyscrasia, nephritis or hepatitis. Clinical response was evaluated in patients who had taken the cycloalkyl urea drugs for as long as seven months or as short a period as one month. Adverse reactions were generaly not encountered. Where it was possible to reduce the dosage of other anti-convulsants, it was evident that the patients had become more alert. No patient reported anorexia, nausea, vomiting, diarrhea, ataxia or rash. Only one patient reported drowsiness.

Eleven patients were given the compound of Example 1 in the form of tablets consisting of the following ingredients:

The particular dosages, the duration of treatment and the results of the therapy are summarized in Table 1 below.

TABLE 1 Degree of seizure control Patient (percent) Duration Daily No. Age Type of epilsepsy (months) dtzsaige Reaction g. Worse 0 50 75 90 100 40 Pmotor 1 40 Pmal and Gmal Drowsy. 12 Gmal 35 Pmotor 4O Gmal 30 Pmal and GmaL. 56 Pmotor 28 Pmal and Gmal 1s Pmal and 6515111..

34 Pmomr andfimall 15 Pmal var. and Gma 1 Pmotor, Psychomotor Pmal, Petit mal; Gmal, Grand mal Pmal van, Petit mal variant.

alcohol was removed under reduced pressure and the solid residue was extracted with 50 ml. of boiling benzene and crystallized from absolute alcohol as white EXAMPLE 4 The cycloalkylurea compounds of Examples 1, 2 and 3, were each administered in the form of tablets containing 0.2 gram of active ingredients per tablet at regular intervals of time to human patients who were epileptics of various types and who had been refractory to the common anti-convulsants in various combinations and in large doses. Each patient was diagnosed by an electroenceph alographic study and the clinical response of the patient evaluated by the change in seizure frequency. In mixed cases, such as those including both petit mal and grand mal seizures, the clinical response was evaluated by the change in seizure frequency of the dominating type of epilepsy. In other words, if a patient had many petit From the tabulated results, it may be seen that of the eleven refractory patients treated with the compound of Example 1, five showed a 75% reduction in seizure frequency in cases of grand mal, petit mal, psychomotor, and petit mal variant epilepsy. All five of these patients had grand mal epilepsy, but in addition two were complicated with petit mal, one with psyohomotor and another with petit mal variant patterns. Referring again to the tabulation of therapeutic results, it may be seen that three additional patients showed 50% improvement in seizure control. In. two other patients there was no improvement and in one who was treated for only one month, the patient complained of drowsiness and reported more seizures than previously experienced. It may be seen that the dosages in the cases that responded favorably to the drug varied from 0.4 gram to 1.3 grams daily.

EXAMPLE 5 Nine patients were treated using the compound of Example 2 in accordance with the procedure set forth in Example 4 above. The daily dosage, the duration and the effects of treatment are summarized in Table 2 below.

From the foregoing tabulated data, it may be seen that of the nine patients treated with the compound of Ex- EXAMPLE 6 The compound of Example 3 was administered to eight patients over periods varying from 1 month to 6 /2 months in accordance with the procedure of Example 4. The results of these treatments are tabulated in Table 3 below.

cellulose, methyl cellulose, sodium alginate, extract of Irish moss, polyvinyl pyrrolidone, water and alcohol (denatured). As disintegrants there may be used, in addition to the corn starch in the above formulation, potato starch, methyl cellulose, agar, bentonite, purified cellulose, natural sponge, various cation exchange resins, alginic acid, guar gum, or citris pulp. Lubricants may be of various types, including, in addition to the magnesium stearate used in the above described formulation, talc, starch, lycopodium, calcium stearate, boric add, sugar, sodium chloride, paraffin, stearic acid, cocoa butter, and soaps. Diluents commonly used include starches and various sugars. Each of the materials mentioned above may be used in combina- TABLE 3 Degree of seizure control Patient (Percent) Duration Daily No. Age Type of epllepsy (months) dosage Worse 0 50 75 90 100 5 1.0 6 0.4 23--" 27 4 0. (3 24" 4% 0.4 25-- 33 6% 0.8 26 4% 0. 5 27 34 Pmotor 1 0. 2 21 Gmal (tuberous sclerosis) 1 6 0.8

From a study of the data tabulated above, it may be seen that one patient was 75% improved upon treatment using 0.8 gram of the compound of Example 3 over a 5 /2 month period. Three other patients were improved using dosages ranging from 0.45 gram to 1.0 gram per day. Three other patients were unimproved and one patient suffering from both grand mal and psychomotor epilepsy showed a greater incidence of seizures following therapy. In the case of the compound of Example 3, the eiiective daily dosage was found to be in the range of from 0.45 gram to 1.0 gram.

The compounds of this invention may be formulated in any of the conventional dosage forms commonly used in the treatment of epilepsy. A preferred form which may be used is tablets containing the active ingredient together with various other materials which facilitate the compounding of the drug, enhance its stability, or affect the convenience of treatment with the drug. For example, the tablets may contain various pharmaceutical adjuvants including disintegrants, diluents, binders and lubricants.

In the formulation detailed in Example 4, for instance, l-( l-methylcyclohexyl)urea is the active ingredient, corn starch is a disintegrant and diluent, lactose and sucrose are diluents, methyl cellulose is a binder and magnesium stearate is a lubricant.

Various other adjuvants known to those killed in the art may be used for each of the purposes outlined above. For example, commonly used binders may include glucose, gum acacia, gelatin, sucrose, starch, carboxymethyl tion with various other materials depending upon the type of tablet which it is desired to form.

0 The tablets may be prepared by any of the conventional tableting techniques including slugging and wet granulation methods.

Instead of using tablets the compounds which constitute the active ingredient of the anti epileptic compo- 5 sitions of this invention may be formulated as pills, capsules, suppositories, liquid suspensions or parenterals, as well as alcoholic solutions. If desired, the compounds may be formulated in delayed action compositions by the use of enteric coatings and the like.

The precise formulations utilized tor purposes of this invention are not critical depending only upon common usage and considerations of convenience, stability, and ease in handling. The unit dosage form for anti-epileptic therapy can most conveniently be supplied in forms wherein the unit dosage, that is, the amount of active ingredient present, falls within the range of from 0.1 gram to 0.5 gram. It is desirable to administer the unit dosage form to the patient at regular intervals during the course of treatment, such that the patient receives daily at least about 0.4 gram of the active ingredient.

In summary, this invention relates to a process for preventing epileptic seizures, particulanly in patients who are ordinarily refractory to other anti-epileptic therapy, which consists in administering to the patients at least about 0.4

gram daily of an anti-epileptic drug which is one of a series of tertiary alicyclic urea derivatives having the formula CH2 R C 2 NHCONHa wherein n is 2 or 3 and R is lower alkyl. These drugs may be formulated in any convenient unit dosage form for ease of administration.

What is claimed is:

1. A method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients at least about 0.4 gram daily of a member selected from the group consisting of 1-( l'-methylcyclohexy:l)urea, 1-( l'-methylcyclopentyl)urea and 1-( l-ethylcyclopentyl)- urea.

2. A method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients a daily dosage of at least 0.4 gram of a cycloalkyl urea selected from the group consisting of 1-(l'- methylcyclohexyburea, 1-(1'-m'ethylcyclopenyl)urea and 1-(1-ethylcyclopentyl)urea, said cycloalkyl urea being incorporated in a unit dosage form comprising said cycloalkyl urea and a pharmaceutical adjuvant therefor.

3. A pharmaceutical formulaion for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1-methylcyclo-hexyDurea, 1-(l' methylcyclopentyDurea and 1- (1'-ethylcyclopentyl)urea in unit dosage form.

4. A formulation for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1'-methylcyclohexyl)- urea, 1-(1-methylcyclopentyl)urea and 1-(1'-ethylcyclopentyDurea and a pharmaceutical :adjuvant therefor.

No references cited. 

1. A METHOD FOR PREVENTING EPILEPTIC SEIZURES IN EPILEPTIC PATIENTS WHICH COMPRISES ADMINISTERING TO EPILEPTIC PATIENTS AT LEAST ABOUT 0.4 GRAM DAILY OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF 1-(1''-METHYLCYCLOAHEXY) UREA, 1-(1''-METHYLCYCLOPENTYL) UREA AND 1-(1''-ETHYCYELOPENTYL)UREA. 